Sometime
around Valentine's Day 2005, bacteria entered James
Fauerbach. They were a strain with the imposing name
methicillin-resistant Staphylococcus aureus, or
MRSA: common staph germs that had mutated to become much
less vulnerable to the methicillin class of antibiotics,
for years the standard treatment for staph. The variant of
MRSA that found its way into Fauerbach also packed a toxin
called Panton-Valentine leukocidin, or PVL. The combination
of drug resistance and this toxin made the pathogen
unusually dangerous. The germs colonized his body and
waited for an opportunity.

An associate professor of psychiatry and chief psychologist
at the
Johns Hopkins Burn Center, on the Bayview campus,
Fauerbach recalls first feeling sick around February 14 or
15. A few days later, he went to a doctor who, based on his
symptoms, diagnosed influenza. The next day, he had trouble
breathing and felt as tired as he'd ever felt in his life.
When he tried to stand, he was so woozy from oxygen
deprivation that he fell, knocking over furniture. His
alarmed wife, Lynn Fauerbach, made him go to an outpatient
clinic, where he began to cough up blood. The clinic
transferred him to Upper Chesapeake Medical Center in
Belair, Maryland, where he was placed on a ventilator. He
was deteriorating fast.

Fauerbach knew he was in trouble. Before doctors intubated
him, he tried to write a note to his children, Anna and
Adam, but all he could manage was an illegible scrawl. His
condition worsened when the air sacs of his lungs could not
tolerate the forceful puffs of air generated by the
ventilator. Lynn, a nurse with critical care experience,
knew he needed a more sophisticated vent, known as an
oscillator, that would be easier on his lungs. She called
colleagues of her husband and finally found an intensive
care bed and an oscillator for him at Bayview. It was
nearly too late. Fauerbach spent the next 11 days intubated
and in a medically induced coma as doctors fought to keep
him alive through a powerful antibiotic called
vancomycin.

Hopkins infectious
disease specialist Jonathan Zenilman and pulmonologist
Jonathan Sevransky made the diagnosis: a rare disease
called necrotizing pneumonia. Not only were Fauerbach's
lungs filling with fluid, the lung tissue itself was dying,
attacked by the PVL toxin. Influenza had caused
inflammation of his respiratory tract, and the PVL-MRSA
already in his system had then seized its chance to begin
destroying his lungs.

After 11 days, the Bayview physicians thought Fauerbach was
well enough to be taken off the ventilator. Doctors and
nurses who had cared for him stood by his bed as he was
extubated, and when they saw him breathe on his own they
broke into applause. Remembering this, Fauerbach pauses to
fight back tears. During his illness, he lost 30 pounds,
mostly muscle mass, and a few days after his release, a
rare allergic reaction to the vancomycin put him back in
the hospital. His recovery was long. Restoring his lungs to
nearly full function took months. For almost a year he had
trouble concentrating. He recalls sitting in his Bayview
office two or three months after his release from the
hospital, trying to reply to a simple e-mail; it took him
90 minutes. "The weirdest things would happen," he says. "I
would try to type 'dog' and 'bear' would come out. It was
really a strange thing."

No sooner did
science develop penicillin, the first antibiotic, 60 years
ago than bacteria began demonstrating resistance to it.
MRSA, the germ that nearly killed Fauerbach, is but one of
several dangerous drug-resistant (and
pronunciation-resistant) pathogens: vancomycin-resistant
enterococcus (VRE), a particular problem with transplant
patients who have compromised immunity; Clostridium
difficile (C. diff), which can induce fatal diarrhea;
multi-drug resistant Acinetobacter baumannii;
vvancomycin intermediate-resistant Staphylococcus
aureus (VISA), currently rare but worrisome. They are
germs that can live in many places, but mostly they live in
hospitals, where they have become a menace. Last October
the Journal of the American Medical Association
published a startling study of data from nine U.S. cities
and estimated that in 2005, MRSA caused serious invasive
infections in 94,360 hospital patients; 18,650 of them
died. If the estimates were accurate, that meant MRSA
killed, or at least contributed to the deaths of more
people in 2005 than HIV/AIDS, Parkinson's disease, or
emphysema. In the days following the JAMA report,
newspapers quoted epidemiologists saying things like "It is
astounding" and "We should be very worried."

Among the worried is Trish Perl. She's paid to be worried,
as Johns Hopkins
Hospital's director of hospital epidemiology and
infection control. She studies the infectious diseases that
beleaguer hospitals, designs improved systems for disease
surveillance, creates interventions to better contain and
eliminate hospital infections, and persuades physicians,
nurses, technical staff, and administrators that Hopkins
can and needs to do better. Her efforts and those of other
infectious disease specialists throughout the Hopkins
system have led to improvements in the monitoring,
prevention, and treatment of hospital-acquired infections.
But they are up against a vexing, shape-shifting opponent
that, day by day, makes their task ever more
complicated.

As organisms
go, a bacterium could not be simpler: one cell, no nucleus.
A membrane surrounding cytoplasm, some protein-synthesizing
ribosomes, and a single looping strand of DNA. That's it.
But if you study bacteria, it becomes hard not to think of
them as possessing agency. They are obstinate. They are
insidious. They are ingenious. And, says Karen Carroll,
director of microbiology at Johns Hopkins Hospital, "they
are always one step ahead of us."

Each time researchers developed a new class ofantibiotics,pathogens developed
resistance. It was as if antibiotics had hit the
evolutionary gas pedal.

Through a microscope, Staphylococcus aureus looks
like a bit of flung caviar. The bacterium's name comes from
staphyle (grape cluster) + coccos (berry) +
aureus (golden), and an electron micrograph indeed
reveals clusters of yellow, spherical microbes. It has
tended to colonize the inside of the human nose, and the
skin in warm, moist places like the armpit or groin. Thirty
percent of people walk around with S. aureus in
their noses and suffer no ill effects. But if it gets past
the barrier of the skin through injury or an incision, it
can cause no end of trouble: boils, sties, urinary tract
infections, impetigo, pneumonia, sinusitis, mastitis,
phlebitis, meningitis, osteomyelitis, endocarditis,
septicemia, and toxic shock syndrome. Before the advent of
antibiotics, if S. aureus entered the bloodstream,
the patient had an 80 percent chance of dying.

Antibiotics promised an end to that scourge. But in only a
few decades, scientists noticed a distressing pattern: Each
time researchers developed a new class of antibiotics,
pathogens developed resistance. It was as if antibiotics
had hit the evolutionary gas pedal. Physicians turned to
methicillin to fight S. aureus resistant to
penicillin; two years later, British researchers first
isolated strains of S. aureus that were resistant to
methicillin, too. In 1964, physicians began using new drugs
called cephalosporins, which were effective against many
infections, including pneumonia; but E. coli, Klebsiella
pneumoniae, and a genus of bacteria called Enterobacter
quickly "learned" how to fight them off. Out of
pharmaceutical labs came the carbapenem and fluoroquinolone
drugs; within a matter of years they began to lose their
effectiveness against Acinetobacter species and other
microbes.

Bacteria, primitive though they are, have survived more
than 3 billion years because they possess a remarkable
ability to adapt to their environments. They defend
themselves against drugs by a variety of means. One
example: Methicillin kills S. aureus by interfering
with the bacterium's ability to form a cell wall. But
somewhere along the evolutionary fast lane, the staph germ
picked up a gene called mecA, and mecA
reduced methicillin's ability to interfere with S.
aureus' cell wall by a thousandfold. Once the pathogen
had mecA, it had transformed itself into MRSA.

No one knows where S. aureus came by its genetic
augmentation. Bacteria possess a deadly ability to trade
DNA, and not just within their own tribes, so to speak.
After enterococci bacteria developed resistance to
vancomycin, British researchers in 1992 watched in the lab
as the enterococci bugs passed this resistance to S.
aureus. Enterococcus to staphylococcus: pathogenic
allies. As more and more physicians prescribed more and
more antibiotics — sometimes appropriately, sometimes
not — resistant pathogens multiplied.

The first recorded case of MRSA in the United States
occurred in Boston in 1968. Six years later, 2 percent of
all hospital-acquired S. aureus infections were
resistant to methicillin. By 2002, 57 percent of ICU staph
infections were MRSA, and experts believe it's now 70
percent. Other resistant bugs like Acinetobacter, C.
diff, and VRE flourish in hospitals as well. But for
now MRSA is the bigger problem. Says Zenilman, "Most VREs
are not that virulent. The same thing with Acinetobacter.
The bug is there, it's got an antibiotic-resistance profile
which looks horrendous — resistant to everything
— but the bug really is a wuss. It doesn't do much.
It's usually more a colonizer than an invasive kind of bug.
MRSA is a different ball of wax because it causes major
problems when it gets into the bloodstream and organs."

It's
simplistic but not wrong to say that Trish Perl works in a
giant Petri dish. Tertiary care hospitals like Hopkins are
incubators for resistant pathogens. Hopkins cares for very
sick people, plus it does a lot of major surgery. All that
illness and all those invasive procedures mean every day
Hopkins physicians contend with infections. Infections
require application of antibiotics, which inevitably create
hothouse conditions for developing more drug-resistant
pathogens. And those pathogens get around to counter tops,
door knobs, bed rails. They find their way on to patients'
skin. They hitch a ride on physicians, surgeons, nurses,
medical technicians, custodial staff, and visitors,
transported to new surfaces and new people. Finally, they
end up in patients' bodies through incisions, intravenous
central lines, medical hardware, and catheters.

When Perl came to Hopkins in 1996, the hospital had an
infection control program that, she says, met regulatory
requirements but did not encourage either preventive action
or interventions that targeted specific problems. No sooner
had she settled in than the hospital experienced a number
of infections among transplant patients from VRE, an
intestinal germ or "gut bug." That got her attention and
she began to investigate drug-resistant infections in the
various hospital units. Perl had come from the University
of Iowa School of Medicine, which had few problems of this
sort. "I was quite surprised by the burden of disease
here," she says. "I was told, 'Well, our patients here are
sicker.' But I was a doc, too, and I looked around and I
didn't think our transplant patients were any sicker than
the transplant patients I'd seen in my previous job." She
studied the VRE outbreak and hospital practices at Hopkins
and believed she saw ways to decrease incidence of the
infection among transplant patients. She worked on another
project in the hematologic malignancy service and decreased
not only infections but bacterial colonizations. As she
began to hear about other interesting pathogens in the
hospital, she decided Hopkins needed to do better
identifying emerging problems. "It's one thing to just
measure, but the most effective infection prevention was
doing interventions to actually decrease problems."

Perl and her team, which includes epidemiologists,
infection control specialists, and the hospital's director
of antibiotic management, invested several years in
research to amass evidence of problems at the hospital.
Some of the early data came from testing various hospital
surfaces. They found drug-resistant germs everywhere. One
study of frequently touched surfaces, such as door knobs,
found 9 percent colonized by MRSA, 24 percent by VRE, and
37 percent by C. diff. Researchers also checked
surfaces that only health care workers, not patients, would
touch, and found one-third colonized by MRSA and 36 percent
by VRE.

Various surfaces at the hospital were only part of the
problem. Nobody knew how many people there at any given
time were carrying infectious microbes, including
drug-resistant strains. This lack of knowledge was not
confined to Hopkins. "There are multiple surveillance
systems throughout the world," Perl says. "You get snippets
from each one. Some are focused on everything that comes
into the microbiology lab. Some are more focused on
infections acquired within acute-care hospitals. But they
all have limitations. [So] there are various guesstimates
of how prevalent these organisms are." The U.S. Centers for
Disease Control (CDC) studied hospital-acquired infections,
known in the business as nosocomial infections, recorded in
2002. It found 1.7 million, resulting in 98,987 deaths.

To gain more control over health care-associated
infections, Hopkins had to do more to identify colonized
patients. If someone became ill from an infection, that was
recorded, but Perl knew that data based on cultures taken
from sick patients significantly underestimated the amount
of disease. "A clinical culture is the top part of the
iceberg," she says. "We have a huge reservoir [of germs]
underneath the water, not seen in clinical cultures because
these people are just colonized and it's not causing
infection. But the risk of transmission is equal if you're
colonized versus infected."

Perl and her colleagues convinced various units of the
hospital to enact more stringent surveillance procedures.
First they concentrated on the most high-risk units: the
surgical ICU, medical ICU, and HIV ward. After their
research found problems in other intensive-care units, they
broadened surveillance. For example, Aaron Milstone, a
Hopkins assistant professor of pediatric infectious
diseases, in 2006 repeated a study of the pediatrics ICU
that had been done in 2001. He found the rate of children
in the PICU colonized by VRE had nearly doubled in five
years; colonization by MRSA had gone up fourfold. Hopkins
Hospital now swabs the nose of every person admitted to any
of its intensive-care units, not just on admission but
every seven days. Anyone found to be colonized by a
drug-resistant strain is immediately isolated.

By these measures, Hopkins made progress against its
infection problem. But MRSA, the deadliest drug-resistant
germ, was not at rest. It was evolving new strains, finding
new places to reside, and new hosts to colonize and
infect.

In 1981,
physicians began to notice MRSA infections among
intravenous drug users in Detroit. Some, but not all, had
been hospitalized recently. Then people who had not been
anywhere near a hospital began acquiring staph infections,
and when researchers cultured them they found MRSA, but not
the same MRSA found in hospitals. These were different
strains. For three decades, the problem of drug-resistant
pathogens had been almost entirely confined to hospitals.
Now the pathogen appeared to be loose in communities. In
most cases, the germs caused skin problems like boils
— painful but treatable. But there were
well-publicized fatalities, first in North Dakota and
Minnesota in 1997 and 1999. One day in 2007, Ashton Bonds,
a healthy 17-year-old senior at Staunton River High School
in Virginia, complained of pain in his side. Twelve days
later he was dead from MRSA-induced multi-organ failure
that ruined his kidneys, liver, lungs, and heart. That same
month, a pre-schooler in New Hampshire, Catherine Bentley,
and an 11-year-old, Shae Kiernan of Mississippi, died from
MRSA infections. For a week or two last October, it was
hard to find a daily newspaper that did not have a
front-page story about drug-resistant staph. Reporters dug
up earlier reports, less noticed at the time, of staph
infection outbreaks among football players at the
University of Southern California, and members of the St.
Louis Rams of the National Football League and the Boston
Celtics of the National Basketball Association. Although
fatal infections due to MRSA in otherwise healthy people
were extremely rare, media coverage scared parents with the
idea that "superbugs" lurked in school locker rooms and who
knew where else.

Epidemiologists began gathering and studying data on the
new community-acquired infections, called CA-MRSA. They
found that congested cities with large populations of urban
poor — Detroit, Atlanta, Baltimore, Chicago —
recorded high rates of staph infection. Zenilman has seen
it at Bayview, where he estimates 25 to 35 percent of the
outpatient visits to the infectious diseases clinic are for
recurring cellulitis caused by staph infections. "These
people are miserable," he says. "You get recurring boils
that can be difficult to control. Because it's spread
through casual contact, you can have kids, relatives who
besides being treated have to change the way they live: no
sharing of bath towels, of soap. If you have teenagers in
the house, that's not easy to implement."

Jason Farley, a Hopkins nurse practitioner and doctoral
candidate specializing in infectious diseases, tested men
brought into the Baltimore City prison. He found 40 percent
of them colonized by S. aureus and 15.8 percent by
MRSA. Prisons, like hospitals, are excellent places for
transmission of infectious agents, so it might have seemed
likely that Farley would find lots of MRSA colonization
there. But among men never previously arrested, a greater
percentage (16.4) had been colonized by MRSA, which
indicated how many drug-resistant germs were out in the
community. Of additional concern, people now were bringing
CA-MRSA from the community into the hospital.

Staphylococcus aureus and other bacteria also took
evolutionary advantage of the complex network that is the
U.S. health system. If sick people went into the hospital
and stayed until they were well, pathogens like MRSA, VRE,
or C. diff could possibly be contained there. But a
seriously ill patient might move through four or five
different facilities. Says Perl, "Both MRSA and VRE have
been introduced into more non-traditional health care
settings because of the movement of patients. [First]
they're here in an acute-care setting. Then more and more
we're pushing sicker patients into rehabilitation
facilities. Then they may go into a long-term care
facility, then they may cycle back to acute care." So what
had been a problem mostly for tertiary care hospitals like
Hopkins became a problem for dialysis centers and
outpatient clinics and assisted-living care centers.

For three decades, the problem of drug-resistantpathogens
had been almost entirely confined to hospitals. Now the
pathogen appeared to be loose in
communities.

Perl was senior author on a 2006 study that screened 1,600
newly admitted patients in five Hopkins ICUs. All had been
in a nursing home or long-term care facility sometime
within six months of admission to Hopkins. The data showed
that these patients were 12 times more likely to be
colonized with multi-drug-resistant Acinetobacter. If they
were wheelchair- or bed-bound due to paralysis, they were
22 times more likely to be colonized. Among the patients
carrying Acinetobacter, 62 percent also had been colonized
by MRSA, 77 percent by VRE, and 39 percent by a pathogen
with the jawbreaker name extended-spectrum beta-lactamase
gram-negative bacteria. As a result of the study, Hopkins
plans to begin testing every incoming patient who has been
in a nursing home, and isolating them until the test
results come back from the lab.

Carroll, the hospital's chief microbiologist, says, "The
crux of the problem is that we're dealing with a community
epidemic that has to be approached from a lot of different
ways. We need to stress that people should not
self-manipulate lesions. They need to come in at the first
signs of infection. They need hand washing — the
simple things that people can do. In the hospital, the
biggest question is, should we screen everyone who walks
through the door for admission? For me, as a
microbiologist, that would present a huge burden because
that will double, maybe triple, the samples we receive. But
if that's what it takes to reduce transmission, we're just
going to have to say that we need to do it."

Once an
infection like MRSA is found, a patient can be isolated and
treated. For the hospital, that's not the hard part. The
hard part is containing and eradicating the pathogen.
Physicians, nurses, therapists, and technicians carry germs
from person to person on their white coats, on instruments
like stethoscopes, and especially on their hands. The
single most effective method of preventing transmission is
also the simplest: hand washing. If only people would do
it.

Study after study has found that health care practitioners
are lax about observing protocols for washing hands with
soap or alcohol-based gels like Purell. In 2006, The New
York Times quoted Australian research that first asked
physicians about their hand washing; 73 percent of the
respondents said they properly followed protocols.
Researchers then observed actual practice and found that
true compliance was a dismal 9 percent. Perl once sent
students from the
Bloomberg School of Public Health to discretely observe
hand washing in the hospital; they found proper compliance
was around 30 percent. A University of Maryland study in
2007 noted that 65 percent of physicians and other
practitioners reported not having worn a newly laundered
white coat in at least a week; 16 percent had not done so
for a month.

Why aren't health care professionals more conscientious?
Sometimes the situation — a crashing patient, for
example, or a beeping ventilator — demands an instant
response with no time for following hygiene protocols. But
Perl encounters a surprising number who still do not
understand the importance. She says, "There are still
people out there who look at me and say, 'Is it really
important that I wash my hands?' I say, 'Well of course it
is,' and I try to show them the data, but in my mind I'm
thinking, and what planet are you on?"

Getting hands clean is a straightforward business. Getting
the environment clean is not. No one knows how to
decolonize a hospital, or if it even can be done. Cleaning
crews face an immense task trying to kill every last
microbe on every surface. Especially problematic are
high-technology components that no one wants to be
responsible for, such as computer keyboards. Says Perl,
"Environmental services doesn't want to touch them because
they get in trouble if they break anything. The nurses
don't consider it their job. The physicians certainly
aren't going to clean anything. So who is responsible?"

Perl and technicians from a British company recently tested
new machinery that aerosolizes hydrogen peroxide and
disperses it throughout a room. "We bombed the SICU," Perl
says, referring to the surgical ICU, one of the units where
the test took place. "It was so cool." She is waiting for
results on the test's effectiveness.

Last November, Johns Hopkins Medicine launched the WIPES
campaign to persuade hospital personnel of their role in
containing and eradicating infectious agents. WIPES is an
acronym for five aspects of the battle against
drug-resistant pathogens: washing hands, identifying and
isolating infected or colonized patients, precautions taken
(like use of gowns, gloves, and masks in isolation rooms),
environment cleaned and kept clean, and sharing the
commitment to better hygiene. Posters appeared on the
hospital walls, each one featuring a hospital employee,
including Hopkins Medicine CEO Edward Miller, holding up
his or her (presumably just-washed) hand.

"It's hard to change behavior," Perl says. "It was hard to
get people to wear seat belts. The hand-hygiene stuff is
the same thing. We need to make this so automatic nobody
even thinks twice about it."

The hospital
is making progress on keeping patients healthier. Perl says
that MRSA transmission in the medical intensive care unit
is down 39 percent, and there was only one nosocomial MRSA
bloodstream infection in all ICUs in 2007, down from
approximately three per year before that. "We're seeing
more and more infection coming in, but when we look at our
disease transmission, it's going down, and our infections
are going down. That's a pretty remarkable story to tell.
We can at least modulate what happens to a vulnerable
patient population." Meanwhile, she keeps studying new
interventions. Sara Cosgrove, the hospital's director of
antibiotic management, monitors use in the hospital and
advises physicians on avoiding inappropriate prescriptions
that will only hasten the evolution of new resistant
strains. Carroll in the microbiology lab remains vigilant
for new germs finding their way into the hospital.

Drug-resistant gram-negative
bacteria are likely the emerging pathogens of the next 10
to 15 years. "Some of them are extremely scary," says Trish
Perl.

Because that will surely happen. Scientists have identified
a new, more lethal strain of C. diff, and a variant
of VRE that resists the drug linezolid. Vancomycin is not
yet exhausted for use when methicillin and others no longer
work. But cases of VRSA (S. aureus resistant to
vancomycin) have turned up — only about 100 so far
and none at Hopkins, but most infectious disease
specialists believe that it's only a matter of time. There
are a couple of new drugs that can be used in those cases,
but for now they are the end of the line. Research and
development of new antibiotics has not been a priority of
pharmaceutical companies for many years now. They are
expensive to develop, require difficult and expensive
clinical trials before they can be brought to market, and
they don't promise the same returns as drugs like Viagra or
medications used by people infected with HIV. Invent an
antibiotic and you have something a patient might need for
two weeks. Create an effective HIV or rheumatoid arthritis
medication and you have a customer for decades.

Even more worrisome for infectious disease researchers are
emergent strains of drug-resistant gram-negative bacteria.
Microbes are designated gram positive or gram negative
depending on how they respond to the gram stains used to
examine them in laboratories. That sounds like a benign
distinction, but it's not. The resistance mechanisms of
gram-negative germs are far more complicated than those of
gram-positive bacteria like MRSA; for example, some
gram-negative pathogens can produce enzymes that render
entire classes of antibiotics ineffective. Some can
actually pump an antibiotic back out of a cell. Perl says,
"We think these are going to be the emerging pathogens of
the next 10 to 15 years, and some of them are extremely
scary." Carroll recently found a case of resistant
gram-negative infection at Hopkins when she isolated an
organism from a liver-transplant patient. The organism was
using an enzyme, carbapenemase, to armor itself against all
the carbapenum antibiotics. "It was resistant to everything
we've tested down here except for one drug, out of 20
agents," she says.

Part of what most scares epidemiologists about
drug-resistant gram-negative pathogens is that
pharmaceutical companies and other research institutions
have done little to develop drugs to fight them. There is
nothing in the pipeline. Corporate priorities, research
funding, public concern, and health care practice are not
yet aligned to face this new threat, and may never be. But
everyone knows the new germs are coming. Pathogens like
MRSA are implacable — not just single-celled but
single-minded. Evolution never rests.